A class of compounds of the formula: ##STR1## wherein, ##STR2## R.sub.1 is wherein p if 0 to 2; m is 0 to 4; and n is 0 to 5; X is 0, S, SO, SO.sub.2, CO, CHCN, CH.sub.2 or C=NR.sub.6 where R.sub.6 is hydrogen, loweralkyl, hydroxy, loweralkoxy, amino, loweralkylamino, diloweralkylamino or cyano; and,
R.sub.4 and R.sub.5 are independently halogen, cyano, trifluoromethyl, loweralkanoyl, nitro, loweralkyl, loweralkoxy, carboxy, lower carbalboxy, trifluoromethoxy, acetamido, loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl; PA0 R.sub.2 is amino, mono or diloweralkyl amino, acetaamido, acetimido, ureido, formamido, formimido or guanidino; and PA0 R.sub.3 is carbamoyl, cyano, carbazoyl, amidino or N-hydroxycarbamoyl; wherein said loweralkyl, loweralkyl containing loweralkoxy and loweralkanoyl groups contain from 1 to 3 carbon atoms, have been determined to be useful for inhibiting proliferation, and invasion and metastasis of malignant tumor cells. Invasion and metastasis, the hallmark of malignancy, is responsible for the lethal effects of cancer. Invasion and locomotion are properties of cancer cells distinct from growth potential. Agents which interfere with these functions selectively in malignant cells have use as agents to prevent or slow metastasis. The compound L651582, (Merck Research Laboratories, U.S. Pat. No. 4,590,201), originally designed as a coccidiostat, was shown previously to inhibit cellular proliferation of normal cells.
In vitro, L651582 inhibited 5-phosphoribosyl pyrophosphate (PRPP) synthesis, and lowered incorporation of formate, hypoxanthine, and adenine without directly inhibiting PRPP synthetase or other enzymes of the de novo and salvage nucleoside synthesis pathways.
Previous data suggested that L651582 inhibits proliferation and inflammation by affecting the biochemical pathways necessary for signal processing in the cell. It is an indirect blocker of the effector enzymes which produce the second messengers necessary to induce growth. These membrane-bound enzymes are activated by coupling to guanine nucleotide binding proteins (G proteins). The antiproliferative effect may be a consequence of the inhibition of those G-protein pathways which mediate the actions of growth factors such as PDGF and TGF.alpha. in initiating hydrolysis of the phosphatidyl inositols (Berridge, Ann Rev Biochem, 1987; Allende, FASEB J, 1988; Neer & Clapham, Nature, 1988). The products, inositol trisphosphate and diacylglycerol, stimulate growth by producing changes in intracellular calcium, and intracellular pH, respectively. Data from the inventors' studies indicated that a similar G protein pathway may be required for tumor cell motility, directed migration and invasion. Collectively, the data on the mechanism of action of L651582 led the inventors to propose that L651582 prevents the receptor activation of G proteins, and/or inhibits a class of G proteins from stimulating the effector enzymes necessary for cellular pathways required for cancer, proliferation, invasion and metastasis.